Doubly stereoconvergent construction of vicinal all-carbon quaternary and tertiary stereocenters by Cu/Mg-catalyzed propargylic substitution

The construction of vicinal, congested stereocenters with high selectivities is of general utility in chemistry. To build two such stereocenters in one step from readily available starting materials is very desirable, but remains challenging. We report here a doubly stereoconvergent, Cu/Mg-catalyzed asymmetric propargylic substitution reaction to convert simple starting materials to products with vicinal tertiary and all-carbon quaternary stereocenters in high yields and excellent diastereo- and enantioselectivities. Both the nucleophiles and the electrophiles employed in this transformation are racemic. This reaction uses earth abundant metal catalysts, operates under ambient conditions, and demonstrates broad substrate scope. The products of this reaction are functional group rich and synthetically versatile. Key to the success of this development is the devise of a Cu/Mg dual catalytic system and the identification of a bulky tridentate pyridinebisimidazoline (PyBim) ligand.

V icinal stereocenters are prevalent in naturally occurring products and pharmaceutical agents (Fig. 1a), and therefore, the stereoselective construction of these structural units represents a subject of a longstanding interest in chemistry 1 . Traditional approaches usually establish the two stereocenters sequentially, which thus require multistep manipulations. A conceptually straightforward and efficient approach to access vicinal stereocenters is by doubly stereoconvergent 2-4 C-C bondforming reactions, such as the ones depicted in Fig. 1b. In this case, racemic compounds 1 and 2 are each converted to prochiral intermediates, whose subsequent combination affords the stereochemically defined product 3 with two stereocenters. In practice, however, the requirement to simultaneously control the relative and absolute configurations during the key C-C bondforming event presents significant difficulties. This task becomes more challenging if an all-carbon quaternary center is involved, as a result of the increased steric repulsion. The challenge further escalates if none of the two stereocenters is embedded in a cycle, due to the enhanced conformational flexibility [5][6][7] .
Notably, however, for most of the products 3 accessed by the above AAS-based methods, the R 4 substituent (carried from electrophile 2) is limited to aryl or alkenyl groups. These advancements notwithstanding, general methods for building vicinal acyclic, congested stereodiads remain highly needed in synthesis. Ideally, a reaction may employ economical and simple catalysts and at the same time accommodate the broad scope of nucleophiles and electrophiles. Our group [21][22][23][24] has been interested in the copper-catalyzed asymmetric propargylic substitution (APS) reactions [25][26][27][28][29][30][31][32][33][34][35][36][37][38] . In terms of bond disconnection, the metal-catalyzed APS reactions are analogous to the AAS reactions. In terms of synthetic utility, the terminal alkyne group installed by the APS reaction is arguably the most versatile 39 24 . This feature may have rendered expanding the scope of nucleophiles a difficult task. Regardless, through developing new catalytic systems, remarkable progress has been achieved in this field. For example, we 21,22,24 and the Nishibayashi group 41 have realized asymmetric propargylation of aliphatic alcohols, a class of nucleophiles previously considered inactive in this transformation.
In continuation of our effort in this field, we wonder if we could employ the simple, linear 1,3-dicarbonyl based nucleophiles (e.g., 4) in the Cu-catalyzed APS reactions (cf. Fig. 1c, 4 + 5 to 6, via 8 and 9). Once realized, this would represent a general tool to construct acyclic, vicinal tertiary, and all-carbon quaternary centers. Furthermore, by facile functional group interconversions of the terminal alkyne group installed, a broad scope of derivatives could be readily accessed. We reasoned that the skinny nature of the alkyne substituent in 5 (and 9) could, to some extent, ameliorate the steric repulsion between both reactants 42 . If 4 could be deprotonated under mild conditions, the resulting soft nucleophile 8 should be able to trap 9 effectively. However, a preeminent challenge lies in how to control the configuration of the acyclic, all-carbon quaternary center in 6: the prochiral nucleophilic center in 8 is quite distant from the chiral environment exerted by the ligands in 9. Previous related studies had to employ cyclic nucleophiles such as 2-indolones to ensure high diastereoselectivities 43 .
In this work, we develop a Cu/Mg-dual catalytic system for a highly diastereoselective and enantioselective propargylation of  simple, linear 1,3-dicarbonyl compounds (Fig. 1c). We establish that the use of a bulky ligand for Cu-catalyst and Mg(O t Bu) 2 as a base is vital for the efficiency and selectivity of this process. As key advantages of this method, it employs non-precious metal catalysts, and readily available reagents/substrates, and demonstrates significant scope with respect to both reaction partners. Importantly, the R group in electrophile 5 could be either aryl or alkyl in nature. The terminal alkyne-containing products 6 could be smoothly converted to other classes of compounds (6-7), further adding to its synthetic utility.

Results
Reaction optimization. To commence our investigation, we used propargyl carbonate 10a and β-keto ester 11a as model substrates (Fig. 2). Not surprisingly, under the "classical" Cu-catalyzed APS reaction conditions [Cu(CH 3 CN) 4 BF 4 as the catalyst precursor, L1 as ligand, and i Pr 2 NEt as base], product 12 was formed, but with low yield and poor diastereoselectivity (entry 1). We then focused our efforts to improve the efficiency and selectivity of this process. We first considered strategies to restrict the rotational flexibility of the nucleophile 11a. Along this line, we investigated transformation. As shown in Fig. 3, a variety of propargyl carbonates could be employed as electrophiles. For example, the aryl group at the propargylic position could be either electron-rich (14e, 14l) or electron-deficient (14a, 14g). Those bearing a substituent at the ortho position (14f) or containing bicyclic ring systems (14i, 14l-m) partook in the reaction smoothly. Functional groups such as aryl halides (14b-c, 14h), boronic acid esters (14d), and cyano (14g) are compatible with the reaction conditions. These functional groups in products are useful handles for further derivatizations. Importantly, pharmaceutically relevant heterocycles, including furans (14j), thiophenes (14k), thiazoles (14n), benzodioxanes (14l), pyridines (14o), and indoles (14m) could also be incorporated. Lastly, we show that the substituent at the propargylic center is not limited to aryls, and those bearing alkyl groups can be employed (14p-q) under slightly modified conditions. We then examined the scope with respect to the nucleophiles (Fig. 4). To our delight, both β-ketoesters (15a-m) and malonate esters (15o-u) are tolerated by this reaction. Again, various (hetero)aryl groups of different electronic properties and substitution patterns can be incorporated. Notably, pyridine rings (15f) and chromones (15g) are well accommodated. Moreover, various alkyl substituents are allowed. In addition, alkene groups (15e, 15r) are also compatible with our conditions. Even the allyl ester group in 15t, a potent reacting functionality in the TMcatalyzed AAS reaction, is completely inert under our conditions, highlighting the mechanistic distinction between the AAS and the APS reactions. Particularly noteworthy is the selective formation of product 15k, which contains a tertiary fluoride: methods to prepare fluorine-containing stereocenters remain underdeveloped but highly needed 49 . Nucleophiles bearing three different carbonyl groups (15l, 15m) were also examined. Interestingly, while product 15l was obtained with excellent diastereo-and enantioselectivities, 15m was formed in poor selectivities. Reactions employing 1,3-diketone nucleophiles proceeded with good efficiency but low diastereoselectivites (15n). Regardless, we show this reaction could be carried out on a gram-scale under slightly modified conditions, with no notable erosion of yield and stereoselectivities (15o).
Product derivatization. To further demonstrate the synthetic utility of this method, we performed product derivatization reactions shown in Fig. 5. First, treatment of 12 with pinacolborane (H-BPin) in the presence of HZrCp 2 Cl led to vinyl boronic acid ester 16a 50 . Alkyne 12 could also undergo [3 + 2] cycloadditions with the in situ generated nitrile oxides, to afford 1,2-oxazoles 16b 51 . Further, alkyne 15o partook in an annulation reaction to give the indole 16c 52 . Treating 15o with basic conditions generated allene 16d 53 . Moreover, alkyne 15o could participate in a Sonagashira coupling with methyl 4-iodobenzoate, leading to 16e 54 . The CuAAC reaction 40 of 15o with anti-HIV drug Zidovudine resulted in 16f with excellent efficiency. Notably, selective amination 55 of 12 could be achieved using methylurea with NaOMe employed as a base. Finally, treatment of 15t with pyrrolidine in the presence of Pd(PPh 3 ) 4 triggered a deallylation and a decarboxylation cascade 56 , yielding product 18 that bear contiguous tertiary stereocenters in good diastereo-and enantioselectivities. The synthetic versatility of these products adds to the utility of our current method.
Mechanistic studies. To explain the observed diastereoselectivities of our reaction, we proposed the stereochemical model in Fig. 6a based on experimental results and literature precedence 25,26 . We reason that Mg(O t Bu) 2 activates nucleophiles by deprotonating β-ketoesters to form the cyclic intermediate 20. On the other hand, the copper complex activates electrophiles by forming the copper allenylidene intermediate 19.
Attack of 20 to 19 may adopt a geometry shown in Fig. 6 (see 21), in order to minimize the repulsion between the ligated copper moiety and the large substituent of 20. The use of bulky ligand to complex with Cu(I) helped to better differentiate the two Fig. 6  substituents (R L vs. R S ) in the nucleophiles, leading to higher diastereoselectivities. As shown in Fig. 6b, the reaction employing cyanoester 23 as nucleophile under our standard conditions gave the corresponding product 24 with poor diastereomeric ratio. This is likely because cyanoester 23 could hardly form a cyclic metallic complex (cf. 18) with Mg(O t Bu) 2 , due to the conformational constraints imposed by the linear cyano group. These results provide support for our proposed stereochemical model.

Discussion
In conclusion, we have established a general, mild, enantio-, and diastereoselective method to construct vicinal tertiary and allcarbon quaternary stereocenters from simple starting materials. The method, which exploits the copper-catalyzed asymmetric propargylic substitution reaction, builds two stereocenters simultaneously by a doubly stereoconvergent process and furnishes a broad array of functional group-rich, terminal alkyne-containing products. Critical to the success of this development are the use of a Cu/Mg-dual catalytic system and the use of a bulky, tridentate PyBim-type ligand. The synthetic versatility of products further adds to the power of this method. We anticipate this method will be rapidly adopted to make the challenging stereodiads that are frequently encountered in natural products and drug candidates, and inspire developments of novel Cu-catalyzed APS reactions.

Methods
General procedures for the Cu/Mg-catalyzed propargylation. In an N 2 -filled glovebox, Cu(CH 3 CN) 4 BF 4 (3.2 mg, 0.01 mmol, 5 mol%), L5 (11.0 mg, 0.02 mmol, 10 mol%), and THF (2 mL) were sequentially added to an 8 mL screw cap vial containing a magnetic stirring bar. The mixture was stirred at r.t. for 1 h. Then, propargyl carbonate 10 (0.30 mmol, 1.5 equiv.), 1,3-dicarbonyl compound 11 (0.20 mmol, 1.0 equiv.), and Mg(O t Bu) 2 (0.04 mmol, 0.2 equiv.) were added sequentially, and the resulting mixture was allowed to stir at r.t. for 24 h. After completion, the reaction mixture was quenched by the addition of water. The mixture was extracted with ethyl acetate three times, and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated. The crude product was purified by flash chromatography, dried under vacuum, weighed, and sampled for HPLC analysis.

Data availability
Additional data supporting the findings described in this paper are available in the Supplementary Information. The X-ray crystallographic data for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CDCC 2096688 (14e), CDCC 2096689 (16f), and CDCC 2096692 (a derivative of 18). These data can be obtained free of charge from the Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.uk/data_request/cif).